DOI 10.1002/art.11187

Comment on methotrexate pneumonitisafter initiation of infliximab therapy forrheumatoid arthritis

To the Editor:

We read with great interest the article by Kramer et al (1)because of our recent experience of fatal and fulminantfibrosing alveolitis following a third infusion of infliximabin a patient with rheumatoid arthritis.

The patient, a 72-year-old woman with longstandingrheumatoid arthritis was started on a dosage of 3 mg/kg ofinfliximab in addition to methotrexate (10 mg/week) be-cause of uncontrolled disease activity. She had been takingmethotrexate for 6 years, and her chest radiograph wasnormal prior to starting infliximab therapy. Four weeksafter the third infusion of infliximab, she presented withdyspnea, hypoxia, and fever. Chest radiograph showedbilateral pulmonary infiltrates and a computed tomogra-phy scan of the thorax was consistent with an extensive,active, fibrosing alveolitis. The patient was treated withmethylprednisolone and broad-spectrum antibiotics, buther condition deteriorated and she required ventilation onthe third day after admission. Results of extensive inves-tigations for an infectious etiology, including sputum cul-tures, blood cultures, bronchial washings, and serologywere all negative during her 10 weeks in the intensive careunit. She was eventually weaned off ventilation, but un-fortunately died 2 days later. Post mortem examinationshowed an active fibrosing alveolitis of both lungs with thenormal fine alveolar pattern replaced by type II pneumo-cytes similar to the biopsy findings reported by Kramer etal in case 2 of their article.

This fatal case reinforces the conclusion of Kramer et althat further postmarketing surveillance of infliximab forthis adverse effect is warranted, particularly when used incombination with methotrexate. Fatal pulmonary fibrosishas been previously reported with methotrexate therapy(2), but not with infliximab. Rheumatologists are alreadyalert to the risk of tuberculosis in patients who developrespiratory symptoms while on infliximab therapy (3) butin view of these reports, potential pulmonary toxicity mustalso be considered.

Phillip A. Courtney, MD, MRCPJ. Alderdice, FRCPathE. M. Whitehead, MD, FRCPAntrim Area HospitalAntrim, Northern Ireland

1. Kramer N, Chuzhin Y, Kaufman LD, Ritter JM, Rosenstein ED.Methotrexate pneumonitis after initiation of infliximab therapy

for rheumatoid arthritis. Arthritis Rheum (Arthritis Care Res)2002;47:670–1.

2. Van der Veen MJ, Dekker JJ, Dinant HJ, van Soersbergen RM,Bijlsma JW. Fatal pulmonary fibrosis complicating low dosemethotrexate therapy for rheumatoid arthritis. J Rheumatol1995;22:1766–8.

3. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J,Schwieterman WD, et al. Tuberculosis associated with inflix-imab, a tumor necrosis factor alpha-neutralizing agent. N EnglJ Med 2001;345:1098–104.

DOI 10.1002/art.11188

Reply

To the Editor:

Since publication of our report we have followed anadditional 46 patients with rheumatoid arthritis (RA)treated with infliximab that was added to existing metho-trexate (MTX) therapy at our center, and no new cases ofMTX pneumonitis have been observed. However, in addi-tion to the patient reported in the letter by Courtney et al,we are personally aware of 2 more cases similar to thosethat we originally reported: a 70-year-old woman whodeveloped biopsy documented MTX pneumonitis; and a68-year-old woman (the sister of case 2 from our report)who developed life-threatening interstitial pneumonitisthat was responsive to antibiotics and high-dose cortico-steroid therapy, in whom lung biopsy was not performed.As was observed in the 3 cases in our original report, andthe case cited Courtney et al in his letter, the onset ofpneumonitis occurred shortly after the third dose of inflix-imab added to a stable dose of MTX. The occurrence of thesame syndrome in 2 siblings raises the possibility of animmunogenetic predisposition.

Although the incidence of MTX pneumonitis may not beincreased with the addition of infliximab, the temporalpattern observed in these 6 cases suggests a potential drug-drug interaction. We urge others treating patients with RAto report any similar cases, thereby allowing a more accu-rate estimate of the incidence of MTX pneumonitis inpatients treated with infliximab.

A plausible mechanism by which anti-tumor necrosisfactor (TNF) therapy might play a permissive or syner-gistic role in the expression of MTX pneumonitis wasrecently reported by Kuroki et al (Kuroki M, Noguchi Y,Shimono M, Tomono K, Tashiro T, Obata Y, et al. Re-pression of bleomycin-induced pneumopathy by TNF.J Immunol 2003;170:567–74). In a murine model of bleo-mycin-induced pneumonitis, TNF -/- mice, in comparisonwith TNF �/�, had an accelerated form of bleomycin-induced pneumonitis and pulmonary fibrosis associatedwith deficient apoptosis of infiltrating inflammatory cells.Intratracheal instillation of TNF reversed the apoptotic

Arthritis & Rheumatism (Arthritis Care & Research)Vol. 49, No. 4, August 15, 2003, pp 617–618© 2003, American College of Rheumatology

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defect and prevented the development of interstitialfibrosis.

Neil Kramer, MDYelena Chuzhin, MDLee Kaufman, MDJill Ritter, MDElliot D. Rosenstein, MDArthritis and Rheumatic Disease Center

at St. BarnabasLivingston, NJ

DOI 10.1002/art.11189

More comments on the “fibromyalgia” label

To the Editor:

Dr. White’s reply to my letter “Comment on the Fibro-myalgia Label: More Cons Than Pros” (1) would be appro-priate if fibromyalgia was actually a disease, which Dr.White clearly believes. However, my comments questionthis assumption and mention some of the problems thathave resulted from this simplified point of view. The issuewas first discussed in an excellent 1997 editorial by Win-field in which he notes that “fibromyalgia is not a distinctentity, the American College of Rheumatology fibromyal-gia criteria detect just the tip of the iceberg,” and that“painful tender joints are a measure of general psychologicdistress” (2). In the January 2003 issue of Arthritis & Rheu-

matism, Ehrlich states categorically that “fibromyalgia isnot a diagnosis” and “should not be dignified with namesthat imply disease states (3),” although he does not appearto be aware of how frequently the term is used in ruralareas. More attention should be paid to medical practicesin regions like the rural South where the fibromyalgia labelis often used as a surrogate for a wide spectrum of stress-related psychoneurotic disorders including chronic anxi-ety and depression. Many of these patients have wide-spread pain and tender joints that do satisfy the AmericanCollege of Rheumatology fibromyalgia criteria (4). Sincethese important underlying conditions often go unrecog-nized (as opposed to the fibromyalgia label), just the “tip ofthe iceberg” is all that is seen and treated, frequently withineffective polypharmacy and poor outcomes.

Stephen G. Gelfand, MD, FACP, FACRMyrtle Beach, SC

1. White KP, Harth M, Nielson W, Speechley M, Ostbye T. Replyto comment on the “fibromyalgia” label: more cons than pros[letter]. Arthritis Rhem (Arthritis Care Res) 2003;49:144–-5.

2. Winfield JB. Fibromyalgia: what’s next [editorial]? ArthritisCare Res 1997;10:219–21.

3. Ehrlich G. Fibromyalgia is not a diagnosis: comment on theeditorial by Crofford and Clauw [letter]. Arthritis Rheum 2003;48:276.

4. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C,Goldenberg DL, et al. The American College of Rheumatology1990 criteria for the classification of fibromyalgia: report of themulticenter criteria committee. Arthritis Rheum 1990;33:160–72.

618 Letters